Targeting EGFR/FOXG1-mediated resistance to ONC201 in H3K27M-mutant diffuse midline glioma

在 H3K27M 突变的弥漫性中线神经胶质瘤中靶向 EGFR/FOXG1 介导的 ONC201 耐药性

• 批准号: 10556344
• 负责人: Carl J Koschmann
• 金额: $ 39.61万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556344
• 关键词: Adult; Agonist; Apoptosis; Binding; Bioenergetics; Brain; Brain Stem; Breast Cancer Cell; Cell Death; Cells; Child; Clinical; Clinical Data; Combined Modality Therapy; DNA Binding; DRD2 gene; Data; Databases; Development; Dopamine D2 Receptor; Dopamine Receptor; EGFR inhibition; Epidermal Growth Factor Receptor; FOXG1B gene; Genes; Genetic; Genetic Transcription; Genomics; Glioma; Glycolysis; H3 K27M mutation; Histones; Human; Immunohistochemistry; In Vitro; Induction of Apoptosis; International; Location; Malignant Neoplasms; Mediating; Metabolic Pathway; Mitochondria; Modeling; Molecular; Mus; Mutation; Outcome; Oxidative Phosphorylation; Pathway interactions; Patients; Peptide Hydrolases; Phase; Phenotype; Progression-Free Survivals; Radiation; Reporting; Research; Resistance; Role; Signal Transduction; Site; Stains; Stress; Subgroup; TNF-related apoptosis-inducing ligand; Thalamic structure; Therapeutic; Translations; Work; antagonist; cancer cell; cell type; clinical efficacy; clinical predictors; combinatorial; diffuse midline glioma; glioma cell line; improved; in vivo; knock-down; neoplastic cell; nerve stem cell; patient population; response; transcription factor; tumor; young adult

PROJECT SUMMARY / ABSTRACT Background and long-term objectives: Children and young adults with diffuse midline glioma (DMG) harboring H3K27M mutation rarely survive longer than two years and have no proven therapies beyond radiation. The dopamine receptor DRD2 antagonist ONC201 induces transcription of TNF-related apoptosis- inducing ligand (TRAIL), leading to apoptosis in multiple tumor cell types. ONC201 additionally binds and activates the mitochondrial protease ClpP, resulting in mitochondrial-mediated cell death in breast cancer cells with active oxidative phosphorylation (OXPHOS). ONC201 is in early phase use in H3K27M-DMG, but its mechanism and efficacy remains unknown. In our preliminary data, ONC201 is effective in murine H3 K27M- mutant gliomas. In our unpublished clinical data (n=50 H3K27M patients), ONC201 doubles PFS and overall survival (OS) in some clinical sub-groups (e.g. thalamic H3K27M) with multiple sustained responses. Despite this impressive efficacy in H3K27M-DMG, we do not know how ONC201 works in H3K27M-DMG tumor cells or how to improve responses in resistant tumors. In analysis of tumor sequencing, ONC201 resistance correlates with high expression of EGFR and the brain developmental transcription factor FOXG1. FOXG1 expression is also the strongest negative predictor of ONC201 sensitivity in human glioma cell lines. In order to prioritize which patients should be treated with ONC201 and to generate rationale combination therapies, there is a critical need to elucidate the mechanism of ONC201 sensitivity in H3K27M cells. Our central hypothesis is that ONC201 is effective in H3K27M-DMG tumors with active OXPHOS through targeting of ClpP and that EGFR signaling mediates ONC201 resistance by inactivating OXPHOS via FOXG1. This is based on our preliminary data in K27M-DMG cells, which shows that cells cultured in media that promotes OXPHOS have an improved response to ONC201, and (iii) EGFR knockdown reduces FOXG1 genomic binding and improves ONC201 response. Approach: In Specific Aim 1, we will determine the impact of: (i) ClpP mitochondrial targeting vs. DRD2 antagonism and (ii) glycolysis vs OXPHOS, in the sensitivity of H3K27M-DMG cells to ONC201. In Specific Aim 2, we will determine the role of FOXG1 in H3K27M-DMG bioenergetics. In Specific Aim 3, we will determine the ability of EGFR inhibition to impact ONC201-induced mitochondrial stress in H3K27M-DMG and for baseline EGFR/FOXG1 tumor staining to predict ONC201 response. We expect to define the mechanism by which EGFR and FOXG1 impact mitochondrial bioenergetics and ONC201 sensitivity in H3K27M-DMG tumors. Significance: This contribution is expected to be significant because it will allow clinicians to prioritize which H3K27M-DMG patients should be treated with ONC201 and provide a platform for rationale combinatorial treatments to improve ONC201 resistance. Our translational team will soon open a multi-site international platform trial that can implement the results of this proposal immediately for patients with H3K27M-DMG.

项目摘要/摘要